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Cryptosporidium parvum has an active hypusine biosynthesis pathway
- Source :
- Molecular and biochemical parasitology. 195(1)
- Publication Year :
- 2013
-
Abstract
- The protozoan parasite Cryptosporidium parvum causes severe enteric infection and diarrheal disease with substantial morbidity and mortality in untreated AIDS patients and children in developing or resource-limited countries. No fully effective treatment is available. Hypusination of eIF5A is an important post-translational modification essential for cell proliferation. This modification occurs in a two step process catalyzed by deoxyhypusine synthase (DHS) followed by deoxyhypusine hydroxylase. An ORF of 1086bp was identified in the C. parvum (Cp) genome which encodes for a putative polypeptide of 362 amino acids. The recombinant CpDHS protein was purified to homogeneity and used to probe the enzyme's mechanism, structure, and inhibition profile in a series of kinetic experiments. Sequence analysis and structural modeling of CpDHS were performed to probe differences with respect to the DHS of other species. Unlike Leishmania, Trypanosomes and Entamoeba, Cryptosporidium contains only a single gene for DHS. Phylogenetic analysis shows that CpDHS is more closely related to apicomplexan DHS than kinetoplastid DHS. Important residues that are essential for the functioning of the enzyme including NAD(+) binding residues, spermidine binding residues and the active site lysine are conserved between CpDHS and human DHS. N(1)-guanyl-1,7-diaminoheptane (GC7), a potent inhibitor of DHS caused an effective inhibition of infection and growth of C. parvum in HCT-8 cells.
- Subjects :
- Models, Molecular
Spermidine binding
Molecular Sequence Data
Protozoan Proteins
Cryptosporidiosis
Biology
Article
Microbiology
parasitic diseases
Deoxyhypusine synthase
Humans
Molecular Biology
Phylogeny
chemistry.chemical_classification
Cryptosporidium parvum
Lysine
Active site
Deoxyhypusine Hydroxylase
biology.organism_classification
Biosynthetic Pathways
Enzyme
Biochemistry
chemistry
biology.protein
Parasitology
NAD+ kinase
EIF5A
Subjects
Details
- ISSN :
- 18729428
- Volume :
- 195
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Molecular and biochemical parasitology
- Accession number :
- edsair.doi.dedup.....973e753609740049d333aab5a111ca6c